Recurrent rearrangements of FOS and FOSB define osteoblastoma

Abstract

The transcription factor FOS has long been implicated in the pathogenesis of bone tumours, following the discovery that the viral homologue, v-fos, caused osteosarcoma in laboratory mice. However, mutations of FOS have not been found in human bone-forming tumours. Here, we report recurrent rearrangement of FOS and its paralogue, FOSB, in the most common benign tumours of bone, osteoblastoma and osteoid osteoma. Combining whole-genome DNA and RNA sequences, we find rearrangement of FOS in five tumours and of FOSB in one tumour. Extending our findings into a cohort of 55 cases, using FISH and immunohistochemistry, provide evidence of ubiquitous mutation of FOS or FOSB in osteoblastoma and osteoid osteoma. Overall, our findings reveal a human bone tumour defined by mutations of FOS and FOSB.

Fig. 1

FOS fusions in osteoblastoma. a Clustered break points in FOS. b Central Circos plot showing the clustering of break points in FOS-mutant samples. All structural variants involving chromosome 14 are shown, demonstrating the paucity of genomic rearrangements. Surrounding panels demonstrate normalised RNA-Seq read counts for each fusion partner. Horizontal line segments reflect mean sequencing counts. The arrow above shows the direction of transcription of the fusion. c Retroviral v-fos. d Schematic of FOS break points in benign bone and vascular tumours generating similarity with the murine retroviral transforming v-fos. Subscript numbers from left to right report the length of the transcript to the stop codon and the predicted cleavage and poly-adenylation site, respectively. e FOS immunohistochemistry demonstrating strong nuclear immunoreactivity in FOS-mutant osteoblastoma, PD13482 (centre with zoom inset), Haematoxylin and eosin (H&E) (left), and a clear breakapart of FISH probes surrounding the FOS locus (right)

Fig. 2

FOSB fusion in PD7525. a Schematic of the PPP1R10-FOSB fusion. The PPP1R10 exon 16 splice donor site is skipped, resulting in exonisation of part of the intron. A three-nucleotide non-template sequence at the break point then allows an in-frame PPP1R10-FOSB fusion transcript to be produced. b Annotated schematic of the wild-type FOSB transcript with the published break points in the vascular tumours (pseudomyogenic haemangioendothelioma (PHE), epithelioid haemangioma (EH))